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Intrinsic and extrinsic drivers of Treg fragility in the tumor microenvironment

Overacre, Abigail E (2018) Intrinsic and extrinsic drivers of Treg fragility in the tumor microenvironment. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Regulatory T cells (Tregs) are required to maintain immune homeostasis through suppressive mechanisms. Characterized by the transcription factor Foxp3, they exert function in a variety of ways, including producing adenosine, and secreting suppressive cytokines. While mandatory for prevention of autoimmunity, Tregs contribute to cancer progression by suppressing the anti-tumor immune response. Depletion of the entire Treg pool is not a viable option for therapy, as mice and humans lacking this population succumb to systemic autoimmunity. Therefore, it is critical to uncover novel mechanisms to target Treg function specifically within the tumor microenvironment (TME) and determine means by which they can in turn be regulated or counter-regulated.
Neuropilin-1 (Nrp1) is required to maintain Treg function and stability within the TME through binding of Semaphorin-4a, and when deleted from Tregs, mice show significantly reduced tumor growth or clearance (Appendix A). However, Nrp1 is dispensable for Treg function in the periphery, making this an attractive target in cancer immunotherapy. Interestingly, Nrp1–/– Tregs maintain Foxp3 expression but lose suppressive function, resulting in Treg ‘fragility’, a term I have coined to describe this phenomenon (Chapter 3). Rather, these cells secrete the pro-inflammatory cytokine IFNγ and cripple surrounding WT Tregs, leading to infectious fragility and enhanced anti-tumor immunity. Strikingly, IFNγ-mediated Treg fragility is required for response to PD-1 blockade in mice, and seems to be partially responsible for response to other immunotherapies, including antibodies and vaccines (Chapter 4). Nrp1 also prevents Treg fragility by acting as a driver of Treg metabolic plasticity within the tumor microenvironment. Indeed, while WT Tregs are distinct metabolically in order to survive in a nutrient-depleted environment within the tumor, Nrp1–/– Tregs are dependent on glycolysis (Chapter 5). This is thought to be due to an increase in Hif1α which supports glycolysis and increases IFNγ in Tregs. Lastly, I have shown that Nrp1 supports Treg stability through maintaining hypomethylation at the Foxp3 locus in the tumor microenvironment, as Nrp1–/– Tregs are hypermethylated, but maintain Foxp3 expression (Appendix B).
Taken together, my findings have uncovered new mechanisms that drive Treg fragility in tumors that are critical for response to immunotherapy.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Overacre, Abigail Eoveracre@pitt.eduOVERACRE
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairVignali, Dario AAdvignali@pitt.eduDVIGNALI
Committee MemberFerris, Robert Lferrrl@upmc.edu
Committee MemberButterfield, Lisa Hlhb3@pitt.eduLHB3
Committee MemberLotze, Michael Tmtl5@pitt.eduMTL5
Committee MemberLee, Janet Sleejs3@upmc.edu
Date: 28 February 2018
Date Type: Publication
Defense Date: 20 February 2018
Approval Date: 28 February 2018
Submission Date: 28 February 2018
Access Restriction: 3 year -- Restrict access to University of Pittsburgh for a period of 3 years.
Number of Pages: 146
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: immunology, cancer
Date Deposited: 28 Feb 2018 20:08
Last Modified: 28 Feb 2018 20:08
URI: http://d-scholarship.pitt.edu/id/eprint/33581

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